PET Imaging of Liposomal Glucocorticoids using <sup>89</sup>Zr-oxine: Theranostic Applications in Inflammatory Arthritis
Peter J. Gawne, Fiona Clarke, Keren Turjeman, Andrew P. Cope, Nicholas J. Long, Yechezkel Barenholz, Samantha Y.A. Terry, Rafael T. M. de Rosales
Abstract
The encapsulation of Glucocorticoids (GCs) into long-circulating liposomes (LCLs) is a proven strategy to reduce the side effects of glucocorticoids and improve the treatment of inflammatory diseases, such as rheumatoid arthritis (RA). With the aim of supporting the development of GC-loaded LCLs, and potentially predict patient response to therapy clinically, we evaluated a direct PET imaging radiolabelling approach for preformed GC-LCLs in an animal model of human inflammatory arthritis. Methods: A preformed PEGylated liposomal methylprednisolone hemisuccinate (NSSL-MPS) nanomedicine was radiolabelled using [ 89 Zr]Zr(oxinate)4 ( 89 Zr-oxine), characterised and tracked in vivo using PET imaging in a K/BxN serum-transfer arthritis (STA) mouse model of inflammatory arthritis and non-inflamed controls. Histology and joint size measurements were used to confirm inflammation. The biodistribution of 89 Zr-NSSL-MPS was compared to that of free 89 Zr in the same model. A therapeutic study using NSSL-MPS using the same time points as the PET/CT imaging was carried out. Results: The radiolabelling efficiency of NSSL-MPS with [ 89 Zr]Zr(oxinate)4 was 69 8 %. PET/CT imaging of 89 Zr-NSSL-MPS showed high uptake (3.6 1.5 % ID; 17.4 9.3 % ID/mL) at inflamed joints, with low activity present in non-inflamed joints (0.5 0.1 % ID; 2.7 1.1 % ID/mL). Importantly, a clear correlation between joint swelling and high 89 Zr-NSSL-MPS uptake was observed, which was not observed with free 89 Zr. STA mice receiving a therapeutic dose of NSSL-MPS showed a reduction in inflammation at the time points used for the PET/CT imaging compared with the control group. Conclusions: PET imaging was used for the first time to track a liposomal glucocorticoid, showing high uptake at visible and occult inflamed sites and a good correlation with the degree of inflammation. A subsequent therapeutic response matching imaging time points in the same model demonstrated the potential of this radiolabeling method as a theranostic tool for the prediction of therapeutic responsewith NSSL-MPS and similar nanomedicines -in the treatment of inflammatory diseases